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Malaria Prescription Drug Information for Healthcare Providers

Determine your Patient’s Risk

Malaria is transmitted to humans by the bite of an infective female Anopheles mosquito. All travelers to malaria-risk areas, including infants, children, and former residents of these areas, should take an antimalarial drug to prevent malaria. Malaria is always a serious disease and may be a deadly illness. Inform your patients that fever or flu-like illness, either while traveling or after returning home (for up to 1 year or more) may be malaria and that they should seek immediate medical attention.

Health care providers (HCP) can find information about malaria risk areas, prophylaxis medications, and anti-mosquito measures on the CDC Travelers' Health website: http://wwwn.cdc.gov/travel. The website contains both general traveler’s health precautions plus malaria-specific information. In addition, the current Health Information for International Travel (the Yellow Book) may be viewed. The CDC malaria risk map application is an interactive map which provides information on malaria throughout the world, see http://www.cdc.gov/malaria/risk_map/.

Provide Antimalarial Drug Dosages, Schedules, and Warnings

Advise patients that antimalarial drugs are most effective if taken exactly on schedule without skipping doses and that their drug should be continued post-travel for the most complete protection. Antimalarial drugs should be purchased before travel; drugs purchased overseas may not be manufactured according to United States standards and may not be effective. They may also be dangerous, contain the wrong drug or an incorrect amount of active drug, or be contaminated.

Halofantrine (marketed as Halfan) is widely used overseas to treat malaria. CDC does not recommend the use of Halfan because of serious cardiac complications, including deaths. Travelers should be advised to avoid Halfan unless they have been diagnosed with life-threatening malaria and no other options are immediately available.

Overdosage of antimalarial drugs can be fatal. Parents should be advised to keep drugs in childproof containers out of the reach of children.

Drugs Used in the Prophylaxis of Malaria

(1) Glucose-6-phosphate dehydrogenase. All persons who take primaquine should have a documented normal G6PD level prior to starting the medication.

Travel to areas with Chloroquine-resistant P. falciparum

Atovaquone/proguanil (Malarone™)

Atovaquone/proguanil is a fixed combination of two drugs; in the United States, it is marketed as Malarone. Atovaquone/proguanil prophylaxis should begin 1-2 days before travel to malarious areas and should be taken daily, at the same time each day, while in the malarious area, and daily for 7 days after leaving such areas.

Doxycycline (brand names and generics)

Doxycycline prophylaxis should begin 1-2 days before travel to malarious areas. It should be continued once a day, at the same time each day, during travel in malarious areas, and daily for 4 weeks after the traveler leaves such areas.

Note: There are insufficient data on the antimalarial prophylactic efficacy of related compounds such as minocycline (commonly prescribed for the treatment of acne). Optimally, for patients already on minocycline, it should be discontinued prior to travel and doxycycline started. Minocycline can be restarted after the four weeks of post-exposure doxycycline is completed.

Mefloquine (Lariam™ and generic)

Mefloquine prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued once a week, on the same day each week, during travel to malarious areas, and for 4 weeks after the traveler leaves such areas.

Primaquine

In special circumstances and after consultation with malaria experts available through the Malaria Hotline (770-488-7788) primaquine may be used for prophylaxis.

Note: Travelers must be tested for G6PD deficiency (glucose-6-phosphate-dehydrogenase) and have a documented G6PD level in the normal range before primaquine use. The testing only has to be done once.

Primaquine prophylaxis should begin 1-2 days before travel to the malaria-risk area. It should be continued once a day, at the same time each day, while in the malaria-risk area, and daily for 7 days after leaving the malaria-risk area.

In those who are G6PD deficient, primaquine can cause hemolysis, which can be fatal. Be sure to document a normal G6PD level before prescribing primaquine.

Travel to Areas with Mefloquine-resistant P. falciparum

Mefloquine-resistant P. falciparum is present in eastern Burma (states of Shah, Kayin, and Kayah), the western provinces of Cambodia that border Thailand, and all malaria-risk areas in Thailand. Either atovaquone/proguanil or doxycycline can be used by travelers to these areas.

Travel to Areas with Chloroquine-sensitive P. falciparum

Chloroquine (Aralen™, Plaquenil™, and generic)

In areas where chloroquine-resistant P. falciparum has not been reported, the following drugs can be used: chloroquine phosphate (Aralen and generic), hydroxychloroquine sulfate (Plaquenil), doxycycline, mefloquine, or primaquine. Less evidence exists on hydroxychloroquine sulfate’s effectiveness as an antimalarial drug.

Chloroquine prophylaxis should begin 1-2 weeks before travel to malarious areas. It should be continued once a week, on the same day of the week, during travel to malarious areas and for 4 weeks after a traveler leaves such areas.

Adverse Reactions and Contraindications

Most antimalarial drugs are well-tolerated; most travelers do not need to stop taking their drug because of side effects. However, if the traveler is particularly concerned about side effects, discuss the possibility of starting their drug early (3-4 weeks in advance of their trip). If the drug cannot be tolerated, another antimalarial drug should be prescribed.

Atovaquone/proguanil

The most common adverse effects reported in persons using atovaquone/proguanil for prophylaxis are abdominal pain, nausea, vomiting, and headache. Atovaquone/proguanil should not be used in infants <5kg, pregnant women, women breast-feeding infants <5kg, or patients with severe renal impairment (creatinine clearance <30mL/min). (Updated December 22, 2006)

Chloroquine phosphate and Hydroxychloroquine sulfate

Side effects that can occur include gastrointestinal disturbance, headache, dizziness, blurred vision, insomnia, and pruritus, but generally these effects do not require that the drug be discontinued. High doses of chloroquine, such as those used to treat rheumatoid arthritis, have been associated with retinopathy; this serious side effect appears to be extremely unlikely when chloroquine is used for routine weekly malaria prophylaxis. Chloroquine and related compounds may exacerbate psoriasis.

Doxycycline

Doxycycline can cause sun sensitivity, usually manifested as an exaggerated sunburn reaction. Travelers on doxycycline should be advised to protect themselves by avoiding prolonged sun exposure and by using sunscreen that absorbs long-wave UVA radiation.

Doxycycline use may be associated with an increased frequency of Candida vaginitis. Travelers should be advised to take an over-the-counter yeast medication or a prescription drug or cream.

Gastrointestinal side effects (nausea or vomiting) may be minimized by taking the drug with a meal and a full glass of water. Travelers should be advised not to take doxycycline before going to bed to avoid esophagitis.

Doxycycline should not be taken by persons allergic to tetracyclines, pregnant women, and by children <8 years of age.

Vaccination with the oral typhoid vaccine Ty21a should be delayed for >24 hours after taking a dose of doxycycline.

Mefloquine

Mefloquine has been associated with rare serious adverse reactions (e.g. psychoses or seizures) at prophylactic doses; these reactions are more frequent with the higher doses used for treatment. Other side effects that occur with prophylactic doses include gastrointestinal disturbance, headache, insomnia, abnormal dreams, visual disturbances, depression, anxiety disorder, and dizziness. Other more severe neuropsychiatric disorders occasionally reported during post-marketing surveillance include sensory and motor neuropathies (including parasthesia, tremor, and ataxia), agitation or restlessness, mood changes, panic attacks, forgetfulness, confusion, hallucinations, aggression, paranoia, and encephalopathy. On occasions, psychiatric symptoms have been reported to continue long after mefloquine has been stopped.

During prophylactic use, if psychiatric symptoms such as acute anxiety, depression, restlessness, or confusion occur, these may be considered prodromal to a more serious event. In these cases, the drug must be discontinued and an alternative drug substituted.

Mefloquine is contraindicated for use by travelers with a known hypersensitivity to mefloquine or related compounds (e.g. quinine and quinidine) and in persons with active depression, a recent history of depression, generalized anxiety disorder, psychosis, schizophrenia, or other major psychiatric disorders. Mefloquine is contraindicated in persons with a history of seizures (not including the type of seizure caused by high fever in childhood). It should be used with caution in persons with psychiatric disturbances or a previous history of depression. A review of available data suggests that mefloquine may be used in persons concurrently on beta blockers, if they have no underlying arrhythmia. However, mefloquine is not recommended for persons with cardiac conduction abnormalities. Any traveler receiving a prescription for mefloquine must also receive a copy of the FDA Medication Guide which can be found at the FDA website: http://www.fda.gov/cder/foi/label/2003/19591s19lbl_Lariam.pdf (PDF format only)

Primaquine

The most common adverse event in G6PD-normal persons is gastrointestinal upset if primaquine is taken on an empty stomach—this problem is minimized or eliminated if primaquine is taken with food.

Primaquine can cause hemolysis in G6PD-deficient persons, which can be fatal. Before primaquine is used, G6PD deficiency MUST be ruled out by appropriate laboratory testing.

Changing Medications during Chemoprophylaxis as a Result of Side Effects

Antimalarial drugs have different modes of action that affect the parasite at different stages of the life cycle. If medications need to be changed because of side effects, there are some special considerations. Travelers who start with medications such as mefloquine or doxycycline but must switch to atovaquone/proguanil during or after travel should continue their atovaquone/proguanil for 4 weeks after switching or 1 week after returning, whichever is longer, but not beyond 4 weeks after return.

Assistance with the management of travelers who need to discontinue their antimalarial drug and switch to another is available at the CDC Malaria Hotline (770-488-7788).

Chemoprophylaxis for Infants, Children and Adolescents

Children of any age can contract malaria; all children traveling to a malaria-risk area should take an antimalarial drug. In the United States, antimalarial drugs are available only in tablet form and may taste quite bitter. Pediatric dosages should be carefully calculated based on the child’s current weight; children’s dosages should never exceed adult dosage.

Full-service (compounding) pharmacists can pulverize tablets, weigh out the precise dose, and place the dose in a gelatin capsule. Advise parents to open the gelatin capsule and mix the drug with something sweet such as applesauce, chocolate syrup, or jelly and to give the drug on a full stomach to minimize stomach upset and vomiting. Parents should allow sufficient time before travel to allow preparation of these dosages.

For additional information see Preventing Malaria in Infants and Children.

Overdosage of antimalarial drugs can be fatal. Medication should be stored in childproof containers out of the reach of infants and children.

Chemoprophylaxis during Pregnancy and Lactation

Malaria infection in pregnant women can be more severe than in nonpregnant women. In addition, malaria can increase the risk for adverse pregnancy outcomes, including prematurity, abortion, and stillbirth. Because malaria is such a serious illness in pregnancy and because no chemoprophylactic regimen is completely effective, women who are pregnant or likely to become pregnant should be advised to avoid travel to a malaria-risk area.

If travel cannot be avoided, then use of an effective antimalarial drug is essential.

Travel during Pregnancy to Areas with Chloroquine-sensitive P. falciparum

Chloroquine phosphate or hydroxychloroquine sulfate are recommended for pregnant women traveling to areas with chloroquine-sensitive P. falciparum. Chloroquine has not been found to have any harmful effects on the fetus when used in the recommended doses for weekly prophylaxis.

Travel during Pregnancy to Areas with Chloroquine-resistant P. falciparum

Mefloquine is currently the only medication recommended for prophylaxis during pregnancy. Studies indicate that prophylactic use during second and third trimesters is not associated with adverse fetal or pregnancy outcomes. More limited data suggest it is also safe during the first trimester.

Because of insufficient data regarding the use during pregnancy, atovaquone/proguanil is not currently recommended for the prevention of malaria in pregnant women. Doxycycline is contraindicated during pregnancy because of the known risks of tetracycline on fetal development, including discoloration and dysplasia of the teeth and inhibition of bone growth. Primaquine should not be used during pregnancy because the drug may pass to a G6PD-deficient fetus and cause hemolytic anemia in utero.

Advice on the management of pregnant travelers is available; call the CDC Malaria Hotline at 770-488-7788.

Lactation

Very small amounts of chloroquine and mefloquine are excreted in breast milk; the amount of drug is not sufficient to harm the infant nor is the quantity sufficient to protect the child from malaria. Breastfeeding infants should receive the recommended dosages of antimalarials found in the table above.

Very limited data are available on the use of doxycycline in lactating women; most experts consider the theoretical possibility of adverse events to be remote.

Primaquine should only be given to lactating women if both the woman and her infant have been tested for G6PD deficiency and have documented normal G6PD levels.

Because safety data is not yet available, atovaquone/proguanil is not currently recommended for women breastfeeding infants <5kg. (Updated December 22, 2006)

For additional information, see Preventing Malaria in the Pregnant Woman.

Educate Your Patients on the Signs and Symptoms of Malaria

Advise your patients that they can still contract malaria despite prophylaxis and anti-mosquito measures. Inform travelers that fever or flu-like illness, either while traveling or after returning home (for up to 1 year or more), may be malaria and that they should seek immediate medical evaluation, including thick and thin smears. CDC recommendations for malaria treatment can be found at http://www.cdc.gov/malaria/diagnosis_treatment/treatment.htm

Self-Treatment

Malaria can be effectively treated early in the course of the disease; however, delay of appropriate treatment can have serious or even fatal consequences. Travelers who choose not to take an antimalarial drug or who are on a less than effective regimen (chloroquine in a chloroquine-resistant risk area) or who may be in very remote areas can be given a self-treatment course of atovaquone/proguanil.

Travelers on atovaquone/proguanil as their antimalarial drug regimen should not use atovaquone/proguanil as their self-treatment drug and should use an alternative self-treatment regimen; call the Malaria Hotline (770-488-7788) for advice on the management of travelers who cannot use atovaquone/proguanil for self-treatment.

Presumptive Self Treatment of Malaria

Travelers should be advised to take their presumptive self-treatment promptly if they have a fever, chills, or other influenza-like illness and if professional medical is not available within 24 hours. Travelers should be advised to seek medical care immediately after self-treatment.

Advise Your Patients to Protect Themselves from Mosquito Bites

Malaria is transmitted by the bite of an infective mosquito; these mosquitoes usually bite between dusk and dawn. To avoid being bitten, remain indoors in a screened or air-conditioned area during the peak biting period. If out-of-doors, wear long-sleeved shirts, long pants, and hats. Apply insect repellent (bug spray) to exposed skin.

Choosing an Insect Repellent

For the prevention of malaria, CDC recommends the use of one of four types of insect repellent.

• DEET (Chemical Name: N,N-diethyl-m-toluamide or N,N-diethly-3-methyl-benzamide). Products containing DEET include but are not limited to: Off!, Cutter, Sawyer and Ultrathon.
• Picaridin (KBR 3023, aka Bayrepel, and icaridin outside the US, Chemical Name: 2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1-methylpropyl ester ) Products containing picaridin include but are not limited to: Cutter Advanced, Skin so Soft Bug Guard Plus and Autan (outside the US)
• Oil of Lemon Eucalyptus or PMD (Chemical Name: para-menthane-3,8-diol) the synthesized version of oil of lemon eucalyptus. Products containing OLE and PMD include but are not limited to: Repel
• IR3535 (Chemical Name: 3-[N-Butyl-N-acetyl]-aminopropionic acid, ethyl ester) Products containing IR3535 include but are not limited to: Skin so Soft Bug Guard Plus Expedition

In general, higher concentrations of the active ingredient provide longer duration of protection. Products with ≤10% active ingredient may offer only limited protection, often from 1-2 hours. Products that offer sustained release or controlled release (micro-encapsulated) formulations, even with lower active ingredient concentrations, may provide longer protection times. Studies suggest that concentrations of DEET above ~50% do not offer a marked increase in protection time against mosquitoes (e.g. DEET efficacy tends to plateau at around 50%). Regardless of what product is used, if travelers start to get mosquito bites they should reapply the repellent according to the label instructions or remove themselves from the area with mosquitoes if possible.

Precautions When Using Any Repellent

• Read and follow the directions and precautions on the product label.
• Use only when outdoors and thoroughly wash off the repellent from the skin with soap and water after coming indoors.
• Do not breathe in, swallow, or get repellent into the eyes or mouth. If using a spray product, apply to your face by spraying your hands and rubbing the product carefully over the face, avoiding eyes and mouth.
• Never use repellents on wounds or broken skin.
• Pregnant women should use insect repellent as recommended for other adults. Wash off with soap and water after coming indoors.
• Repellents may be used on infants older than 2 months of age.
• Children under 10 years old should not apply insect repellent themselves. Do not apply to young children’s hands or around their eyes and mouth.

Other Recommended Anti-mosquito Measures

• Travelers should take a flying insect spray on their trip to help clear rooms of mosquitoes. The product should contain a pyrethroid insecticide; these insecticides quickly kill flying insects, including mosquitoes.
• Travelers not staying in well-screened or air-conditioned rooms should sleep under bed nets (mosquito nets), preferably nets treated with the insecticide permethrin. Permethrin both repels and kills mosquitoes as well as other biting insects and ticks. In the United States, permethrin is available as a spray or a liquid (e.g. Permanone ™). Pre-treated nets, permethrin or another insecticide deltamethrin, are available overseas.
• Protect infants (especially infants under 2 months of age not wearing insect repellent) by using a carrier draped with mosquito netting with an elastic edge for a tight fit.
• Clothing, shoes, and camping gear, can also be treated with permethrin. Treated clothing can be repeatedly washed and still repel insects. Some commercial products (clothing) are now available in the United States that have been pretreated with permethrin.